This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with 1,4-disubstituted piperazine derivatives wherein one substituent is a bicyclic fused-ring heterocyclic system comprising furo-, pyrrolo-, cyclo- pentadieno-, and thieno-pyridine ring systems; and the other is an alkylene chain, preferably a butylene chain, bearing a cyclic imide ring or a benzylic carbinol moiety at its terminus. Examples of types of these terminal moieties are depicted below; ##STR1##
A considerable amount of related art has been generated over the past fifteen years, much of which has arisen from the research group of the Bristol-Myers Company. The pertinent related art comprising compounds with CNS activity may be viewed in light of the following general structural formula (1) ##STR2## in which alk is an alkylene chain connnecting the piperazine ring with the cyclic imide group and B is a heterocyclic ring with optional substituents.
Wu, et al., U.S. Pat. Nos. 3,717,634 and 3,907,801 as well as a corresponding Wu, et al., publication--J. Med. Chem., 15, 447-479 (1972)--describe various azaspiro[4.5]-decanedione psychotropic compounds wherein B represents various monocylic heterocycles such as pyridine, pyrimidine, or triazine, all with optional substituents.
Temple, Yevich and Lobeck in U.S. Pat. No. 4,305,944 disclose azaspiro[4.5]decanedione tranquilizing compounds wherein B is a 3-cyanopyridin-2-yl or 3-methoxypyridin-2-yl moiety.
Temple, Yevich and Lobeck report dialkylglutarimide tranquilizing compounds in U.S. Pat. No. 4,361,565 in which B is a 3-cyanopyridin-2-yl ring which may bear a second optional substituent.
Temple and Yeager in U.S. Pat. Nos. 4,367,335 and 4,456,756 disclose antipsychotic thiazolidinediones and spirothiazolidinediones wherein B is a 2-pyridinyl ring, either unsubstituted or containing a cyano substituent.
Temple and Yevich in U.S. Pat. Nos. 4,411,901, and 4,452,799 disclosed antipsychotic compounds with a variety of cyclic imide and benzylic carbinol moieties wherein B was either benzisothiazole or benzisoxazole ring systems.
Attention is also called to the following.
In U.S. Ser. No. 531,519, filed 9/12/83 and now U.S. Pat. No. 4,524,206, New and Yevich disclose and claim psychotropic succinimide and phthalimide-type compounds wherein B is a 2-pyrimidinyl ring. These compounds demonstrate antianxiety activity.
A series of antipsychotic 1-fluorophenylcarbonyl-, -carbinol-, -ketal-, propy-4-(2-pyrimidinyl)piperazines are disclosed by Yevich and Lobeck in U.S. Pat. No. 4,605,655.
Finally, New, Yevich and Lobeck in U.S. Pat. No. 4,619,930, disclose and claim a series of antipsychotic compounds which contain a variety of cyclic imide moieties and wherein B is a mono- or di-substituted pyridine ring system.
While the psychotropic compounds listed above are generally related to the compounds of the instant invention, they are nonetheless distinguishable thereof structurally on the basis of the B moiety of structural formula 1. Essentially, in the art compounds, B is usually a monocyclic heteroaryl ring with the only examples of bicyclic systems being fused benzo ring heterocyclics, i.e. benzisothiazole or benzisoxazole ring systems. This distinguishes these compounds from the compounds of the present invention in which B is comprised of different classes of fused heterocyclic rings, i.e. furo-, pyrrolo-, cyclopentadieno-, or thieno-pyridine ring systems. The instant compounds may also be distinguished pharmacologically on the basis of psychotropic properties and side effect profiles from the art compounds. In this regard, the compounds of the instant invention possess selective antipsychotic (neuroleptic) activity with serotonin antagonism, and, surprisingly, have low affinities for dopamine receptors which is in contrast to the prior art antipsychotic agents described, supra. In this regard, the instant compounds pharmacologically bear some semblance to the atypical standard neuroleptic agent, clozapine (2), cf: The Merck Index, 10th Edition (1983), page 344, and reference therein. ##STR3## As can be seen, clozapine belongs to the dibenzodiazepine class of psychotropics which bear little structural relationship to the instant series of compounds. Additionally, the instant compounds appear to lack the potential for causing the adverse extrapyramidal symptomatology associated with the chronic administration of currently used antipsychotic agents. Further, selected compounds from the instant series have demonstrated in animal models, the ability to reverse catalepsy resulting from administration of trifluoperazine, a standard neuroleptic agent.